Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats.

Abstract Early manifestations of Alzheimer's disease (AD) include neuroinflammation, disrupted neurotransmission and cognitive deficits. Impairment of the GABAergic system is essentially involved in the pathogenesis of AD. Traditionally, agonists of GABA A receptors at doses above 1 mg/kg are known to possess memory impairing effects. However, we have previously found that GABA A receptor GABA site ligand muscimol at very low doses acted contrary – enhanced spatial learning/memory, as well as prevented neuroinflammation and augmented neurotransmission in AD model rats. Therefore, in the present study we focused on the assessment of the effects of non-sedative – very low (0.05 mg/kg) and moderate (1 mg/kg) – doses of diazepam, a positive allosteric modulator of benzodiazepine site of GABA A receptors. Its effects on spatial learning/memory and brain proteins related to neuroinflammation (GFAP and Iba-1), synaptic plasticity (SYP1), as well as acetylcholine breakdown and GABA biosynthesis were studied. Non-transgenic AD model rats (intracerebroventricular streptozocin injection) were used with the aim to mimic the pre-dementia stage of AD in humans. The obtained data showed that diazepam at both doses protected against streptozocin induced detrimental effects by enhancing spatial learning/memory, preventing neuroinflammation, preserving synaptic plasticity, as well as normalizing the hippocampal and cortical protein expression related to acetylcholine breakdown and GABA biosynthesis. One may suggest that at low and moderate doses diazepam is targeting non-specific, probably allosteric GABA A receptor sites, thus leading to stimulatory effects that can be beneficial for diazepam use in early pre-dementia stages of AD. Highlights • Diazepam (0.05 and 1 mg/kg ip) improved STZ-induced memory deficit in rats. • Both doses of diazepam alleviated STZ-induced astrogliosis. • Diazepam at both doses normalized AChE and GAD67 density. • At 0.05 mg/kg, diazepam preserved hippocampal synaptophysin expression. [ABSTRACT FROM AUTHOR]